Extent of Helical Induction Caused by Introducing α-Aminoisobutyric

Jun 14, 2018 - The preferred conformations of a dodecapeptide composed of l-valine (l-Val) and α-aminoisobutyric acid (Aib) residues, ...
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Article Cite This: ACS Omega 2018, 3, 6395−6399

Extent of Helical Induction Caused by Introducing α‑Aminoisobutyric Acid into an Oligovaline Sequence Genichiro Tsuji,† Takashi Misawa,† Mitsunobu Doi,‡ and Yosuke Demizu*,† †

Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa 210-9501, Japan Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan

‡

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S Supporting Information *

ABSTRACT: The preferred conformations of a dodecapeptide composed of L-valine (L-Val) and α-aminoisobutyric acid (Aib) residues, Boc-(L-Val-L-Val-Aib)4-OMe (3), were analyzed in solution and in the crystalline state. Peptide 3 predominantly folded into a mixture of α- and 310-(P) helical structures in solution and a (P) α helix in the crystalline state.

1. INTRODUCTION In proteins, helices are abundant and important secondary structures, which recognize macromolecules, such as other proteins and DNA. Helical peptides that mimic proteins are capable of inhibiting protein−protein interactions, and a variety of helix-stabilizing methods have been developed to aid the production of such peptides. As representative techniques, the introduction of α,α-disubstituted α-amino acids (dAA)1 or cyclic β-amino acids2 into short oligopeptides and side-chain stapling3 can all help to stabilize helical structures. In particular, α-aminoisobutyric acid (Aib) is the simplest dAA, and it is commonly used as a helical promoter.4 We have previously reported that the introduction of Aib residues into natural amino acid sequences stabilized helical structures. For example, the oligopeptides Boc-(L-Leu-L-Leu-Aib)n-OMe (n = 3 or 4) preferentially form stable right-handed (P) helical structures.5,6 These peptides are able to act as organocatalysts for asymmetric reaction, such as enantioselective epoxidation catalysts of α,βunsaturated ketones6 and Michael addition of a malonate.7 Furthermore, the amphipathic peptides R-(L-Xaa-L-Xaa-Aib)3NH2 (R = FAM-β-Ala and Xaa = Arg or R = H and Xaa = Lys) were also folded into stable helical structures and were used as antimicrobial peptides8 and cell-penetrating peptides,9 respectively. In addition, we have recently reported that the azidolysine (Azl)-based peptide Boc-(L-Azl-L-Azl-Aib)3-OMe formed a stable helical structure, and the azide groups could be replaced with several functional groups via click reactions without influencing the peptide’s helical structure.10 Thus, the insertion of Aib residues into α-amino acid-based oligopeptides is useful for stabilizing helical structures and providing a variety of functions. However, there have not been any reports about the secondary structural changes that occur when Aib residues are introduced into oligopeptides that form extended β-sheet structures. In general, oligopeptides composed of β-branched amino acids, such as valine (Val) and isoleucine (Ile), form βsheet structures with extended conformations. In particular, oligovalines have a strong tendency to form β-sheet conformations.11 In this study, we designed a dodecapeptide © 2018 American Chemical Society

composed of L-Val and Aib residues, Boc-(L-Val-L-Val-Aib)4OMe (3), and analyzed its preferred conformations in solution and in the crystalline state.

2. RESULTS AND DISCUSSION The dodecapeptide Boc-(L-Val-L-Val-Aib)4-OMe (3) was synthesized using conventional solution-phase methods according to a fragment condensation strategy, in which 1-(3dimethylaminopropyl)-3-ethylcarbodiimide (EDC) hydrochloride and 1-hydroxybenzotriazole (HOBt) hydrate were used as coupling reagents. Briefly, alkaline hydrolysis of the tripeptide Boc-L-Val-L-Val-Aib-OMe (1) afforded the acid 1-COOH, whereas Boc deprotection by trifluoroacetic acid furnished the amine 1-NH2. The amine 1-NH2 was coupled with 1-COOH to give the hexapeptide Boc-(L-Val-L-Val-Aib)2-OMe (2). The dodecapeptide 3 was prepared in a manner similar to that used to prepare the hexapeptide (Scheme 1). The dominant conformations of the synthesized peptides 1− 3 in solution were analyzed based on their Fourier transform infrared (FT-IR), 1H nuclear magnetic resonance (NMR), and circular dichroism (CD) spectra. Figure 1 shows the IR spectra of the tri- (1), hexa- (2), and dodecapeptide (3) in the 3200− 3500 cm−1 region (the amide A NH-stretching region) at a peptide concentration of 5.0 mM in CDCl3 solution. In the spectra, the weak bands in the 3425−3438 cm−1 region were assigned to free (solvated) peptide NH groups, and the strong bands in the 3325−3340 cm−1 region were assigned to peptide NH groups with N−H···OC intramolecular hydrogen bonds. These IR spectra are similar to those of helical peptides containing Aib residues.12 In the 1H NMR spectra of the dodecapeptide 3, the Nterminal urethane-type N(1)H proton signal was unambiguously determined by the high-field position but the remaining eleven peptide NH protons could not be assigned. Figure 2 Received: May 17, 2018 Accepted: June 5, 2018 Published: June 14, 2018 6395

DOI: 10.1021/acsomega.8b01030 ACS Omega 2018, 3, 6395−6399

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ACS Omega Scheme 1. Synthesis of Peptides 1−3

high-field positions were sensitive to the addition of DMSO-d6. These results are indicative of a 310- or α-helical structure in solution.13 The CD spectra of the dodecapeptide 3 in 2,2,2trifluoroethanol (TFE) showed negative maxima at 207 and 222 nm indicating that 3 formed a right-handed (P) helical structure. Judging from the R([θ]222/[θ]208) value,14 the secondary structure of 3 (R = 0.64) was a mixture of α- and 310-helical structures (Figure 3). This spectrum is similar to that of Boc-(L-Leu-L-Leu-Aib)4-OMe (R = 0.51).15

Figure 1. IR spectra of peptides 1 (green), 2 (blue), and 3 (red) in CDCl3 solution (peptide concentration: 5.0 mM).

Figure 3. CD spectra of the dodecapeptide 3 (red) and Boc-(L-Leu-LLeu-Aib)4-OMe (black) in TFE solution (peptide concentration: 0.1 mM).

Peptide 3 formed good crystals for X-ray crystallographic analysis after the slow evaporation of methanol/water at room temperature. Its crystal and diffraction parameters, selected backbone and side-chain torsion angles, and intra- and intermolecular hydrogen-bond parameters are listed in the Supporting Information.16−19 The asymmetric unit in 3 contained two (P) α-helical structures with a flipped Cterminal Aib(12) residue (Figure 4a). The conformations of

Figure 2. Plots of chemical shift values of the NH protons of peptide 3 as a function of the concentration of DMSO-d6 (v/v) in CDCl3 solution (peptide concentration: 5.0 mM).

shows a solvent perturbation experiment involving the addition of the strong H-bond acceptor solvent dimethyl sulfoxide (DMSO-d6) [0−10% (v/v)]. Two NH chemical shifts in the 6396

DOI: 10.1021/acsomega.8b01030 ACS Omega 2018, 3, 6395−6399

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ACS Omega

J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 174.6, 171.6, 167.0, 156.1, 80.4, 60.5, 58.3, 56.4, 52.5, 50.2, 30.3, 30.2, 28.3, 24.8, 24.7, 19.3, 19.2, 17.7, 17.5; [HR-ESI(+)TOF] m/z: calcd for C20H37N3O6Na [M + Na]+, 438.2575; found, 438.2591. 4.3. Synthesis of Hexapeptide 2. A solution of the tripeptide Boc-L-Val-L-Val-Aib-OMe (1) (415 mg, 1.0 mmol) and 1 M aqueous NaOH (2.0 mL, 2.0 mmol) in MeOH (10 mL) was stirred at room temperature for 24 h. The solution was neutralized with 1 M aqueous HCl and was extracted with AcOEt. Being dried over Na2SO4 and removing the solvent afforded the tripeptide-carboxylic acid 1-COOH, which was used for the next reaction without further purification. Trifluoroacetic acid (1 mL) was added to a solution of 1 (415 mg, 1.0 mmol) in CH2Cl2 (5 mL), and then the mixture was stirred at room temperature for 5 h. Removing the solvent afforded the crude N-terminal free tripeptide 1-NH2, which was used without further purification. A mixture of EDC (230 mg, 1.2 mmol), HOBt (162 mg, 1.2 mmol), N,N-diisopropylethylamine (418 μL, 2.4 mmol), the above 1-COOH (1.0 mmol), and the above 1-NH2 (1.0 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 3 days. The solution was washed with 3% aqueous HCl, saturated aqueous NaHCO3, and brine, before being dried over Na2SO4. After removing the solvent, the residue was purified by column chromatography on silica gel (n-hexane/AcOEt = 1:5) to give the hexapeptide 2 in 46% yield. Colorless crystals; mp 200−203 °C; [α]24 D = −27.4 (c 0.5, CHCl3); IR (CDCl3, cm−1): 3437, 3340, 2968, 2935, 2875, 1736, 1703, 1665; 1H NMR (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.17 (s, 1H), 6.93 (d, J = 6.8 Hz, 1H), 6.44 (d, J = 5.2 Hz, 1H), 5.01 (d, J = 2.6 Hz, 1H), 4.42 (dd, J = 8.8, 5.2 Hz, 1H), 4.18 (dd, J = 6.4, 4.4 Hz, 1H), 3.95 (dd, J = 4.4 Hz, 1H), 3.82 (dd, J = 4.4, 2.6 Hz, 1H), 3.68 (3H, s), 2.50−2.44 (m, 2H), 2.30−2.20 (m, 2H), 1.53 (3H, s), 1.52 (3H, s), 1.50 (9H, s), 1.50 (3H, s), 1.48 (3H, s), 1.06 (d, J = 6.8 Hz, 6H), 1.05−1.04 (m, 3H), 1.01 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 175.6, 175.2, 172.1, 171.9, 170.9, 170.5, 157.0, 81.8, 62.1, 60.8, 60.0, 58.6, 57.1, 55.8, 52.0, 29.4, 29.2, 28.9, 28.2, 27.5, 25.2, 24.7, 23.7, 19.6, 19.3, 19.2, 18.0, 17.5, 17.4, 17.2; [HR-ESI(+)-TOF] m/z: calcd for C34H62N6O9Na [M + Na]+, 721.4470; found, 721.4502. 4.4. Synthesis of Dodecapeptide 3. The dodecapeptide 3 was prepared using a method similar to that described for the preparation of 2. Yield 35%; colorless crystals; mp 302−304 −1 °C; [α]24 D = −16.9 (c 0.5, CHCl3); IR (CDCl3, cm ): 3425, 1 3325, 2967, 2936, 2876, 1734, 1703, 1656; H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.53−7.51 (m, 3H), 7.21 (d, J = 5.6 Hz, 1H), 7.10 (d, J = 6.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.72 (br s, 1H), 5.39 (br s, 1H), 4.41 (dd, J = 9.0, 5.8 Hz, 1H), 4.25 (dd, J = 7.2, 5.6 Hz, 1H), 3.89−3.84 (m, 3H), 3.82−3.79 (m, 1H), 3.71−3.62 (m, 2H), 3.67 (s, 3H), 2.47−2.36 (m, 2H), 2.29−2.15 (m, 6H), 1.52−1.48 (m, 33H), 1.12−0.97 (m, 48H); 13 C NMR (100 MHz, CDCl3): δ 175.9, 175.9, 175.5, 173.8, 173.8, 173.0, 172.7, 172.6, 172.3, 171.5, 171.0, 157.2, 81.7, 62.9, 62.7, 62.5, 62.3, 60.9, 60.7, 59.2, 57.0, 56.8, 56.6, 55.8, 51.9, 29.8, 29.6, 29.5, 29.2, 29.2, 28.9, 28.3, 27.5, 27.4, 25.2, 24.6, 23.4, 23.3, 23.0, 19.9, 19.7, 19.5, 19.4, 19.4, 19.3, 19.2, 19.1, 19.1, 19.0, 18.9, 18.5, 18.0, 18.0, 17.8; [HR-ESI(+)-TOF] m/z:

Figure 4. (a) X-ray diffraction structure of 3. The methanol molecules have been omitted. (b) Superimposed structures of molecules A (green) and B (blue).

molecules A and B were well-matched, except for small differences in their side-chain conformations (Figure 4b). The mean ϕ and ψ torsion angles of the residues (2−11) were −63.1° and −39.9° for A and −62.6° and −40.7° for B, which are close to those of an ideal (P) α-helix (−60° and −45°, respectively). Regarding the intramolecular hydrogen bonds in molecules A and B, eight i ← i + 4 type hydrogen bonds were observed, respectively. In packing mode, molecules A and B were connected by intermolecular hydrogen bonds via methanol molecules, forming chains with head-to-tail alignments (···A···A···A··· and ···B···B···B···).

3. CONCLUSIONS We designed and synthesized a dodecapeptide-containing L-Val and Aib residues, Boc-(L-Val-L-Val-Aib)4-OMe (3), to investigate the influence of the helical promoter Aib on β-sheet structures. The conformation of 3 was analyzed based on its FT-IR, 1H NMR, and CD spectra in solution and X-ray diffraction analysis in the crystalline state. Peptide 3 predominantly folded into a mixture of α- and 310-(P) helical structures in solution and a (P) α helix in the crystalline state. Although oligopeptides composed of β-branched amino acids form β-sheet structures with extended conformations, the insertion of Aib residues into β-sheet-forming peptide sequences could change the conformations of helical structures. Thus, we revealed that the insertion of Aib residues into oligopeptides not only stabilized their helical structures but also markedly altered their secondary structures (from βsheets to helical structures). Not only helical but also unique secondary structures will be created by the combination of natural L- and/ or D-amino acids and Aib residues,20 and these findings will be invaluable for the de novo design of peptide-based organic and bioorganic molecules. 4. EXPERIMENTAL SECTION 4.1. General. 1H and 13C NMR spectra were recorded at 400 and 100 MHz in CDCl3 (tetramethylsilane as an internal standard). FT-IR spectra were recorded at 1 cm−1 resolution, with an average of 256 scans used for the CDCl3 solution method (0.1 mm path length for NaCl cell). High-resolution mass spectra were recorded with LCMS-IT-TOF spectrometer. CD spectra were recorded using a 1.0 mm path length cell in TFE. 4.2. Synthesis of Tripeptide 1. The tripeptide 1 was prepared by conventional solution-phase peptide synthesis strategy. Colorless crystals; mp 177−179 °C; [α]24 D = −95.7 (c 0.25, CHCl3); IR (CDCl3, cm−1): 3437, 2969, 2934, 2875, 1738, 1705, 1671; 1H NMR (400 MHz, CDCl3): δ 6.66 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.99 (d, J = 7.2 Hz, 1H), 4.21− 4.18 (m, 1H), 3.91 (dd, J = 6.8 Hz, 1H), 3.70 (s, 3H), 2.23− 2.17 (m, 2H), 1.53 (s, 3H), 1.51 (s, 3H), 1.45 (s, 9H), 0.97 (d, 6397

DOI: 10.1021/acsomega.8b01030 ACS Omega 2018, 3, 6395−6399

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ACS Omega calcd for C62H112N12O15Na [M + Na]+, 1287.8262; found, 1287.8333.

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Cornejo, M.; Davis, T. N.; Del Bianco, C.; Aster, J. C.; Blacklow, S. C.; Kung, A. L.; Gilliland, D. G.; Verdine, G. L.; Bradner, J. E. Direct inhibition of the NOTCH transcription factor complex. Nature 2009, 462, 182−188. (c) Oba, M.; Kunitake, M.; Kato, T.; Ueda, A.; Tanaka, M. Enhanced and Prolonged Cell-Penetrating Abilities of ArginineRich Peptides by Introducing Cyclic α,α-Disubstituted α-Amino Acids with Stapling. Bioconjugate Chem. 2017, 28, 1801−1806. (d) LaRochelle, J. R.; Cobb, G. B.; Steinauer, A.; Rhoades, E.; Schepartz, A. Fluorescence Correlation Spectroscopy Reveals Highly Efficient Cytosolic Delivery of Certain Penta-Arg Proteins and Stapled Peptides. J. Am. Chem. Soc. 2015, 137, 2536−2541. (e) Demizu, Y.; Yamagata, N.; Nagoya, S.; Sato, Y.; Doi, M.; Tanaka, M.; Nagasawa, K.; Okuda, H.; Kurihara, M. Enantioselective epoxidation of α,βunsaturated ketones catalyzed by stapled helical L-Leu-based peptides. Tetrahedron 2011, 67, 6155−6165. (4) (a) Lister, F. G. A.; Le Bailly, B. A. F.; Webb, S. J.; Clayden, J. Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor. Nat. Chem. 2017, 9, 420−425. (b) Crisma, M.; Formaggio, F.; Moretto, A.; Toniolo, C. Peptide helices based on α-amino acids. Biopolymers 2006, 84, 3−12. (c) Tonlolo, C.; Benedetti, E. Trends Biochem Sci. 1991, 16, 350−353. (d) Karle, I. L.; Balaram, P. Structural characteristics of α-helical peptide molecules containing Aib residues. Biochemistry 1990, 29, 6747−6756. (e) Ousaka, N.; Takeyama, Y.; Iida, H.; Yashima, E. Chiral information harvesting in dendritic metallopeptides. Nat. Chem. 2011, 3, 856−861. (f) Tsuchiya, K.; Numata, K. Chemoenzymatic synthesis of polypeptides containing the unnatural amino acid 2-aminoisobutyric acid. Chem. Commun. 2017, 53, 7318−7321. (g) Demizu, Y.; Doi, M.; Sato, Y.; Tanaka, M.; Okuda, H.; Kurihara, M. Screw-Sense Control of Helical Oligopeptides Containing Equal Amounts of L- and D-Amino Acids. Chem. Eur. J. 2011, 17, 11107−11109. (5) Demizu, Y.; Doi, M.; Kurihara, M.; Okuda, H.; Nagano, M.; Suemune, H.; Tanaka, M. Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,αdisubstituted α-amino acid as an α-helical inducer. Org. Biomol. Chem. 2011, 9, 3303−3312. (6) Nagano, M.; Doi, M.; Kurihara, M.; Suemune, H.; Tanaka, M. Stabilized α-Helix-Catalyzed Enantioselective Epoxidation of α,βUnsaturated Ketones. Org. Lett. 2010, 12, 3564−3566. (7) Akagawa, K.; Sakai, N.; Kudo, K. Histidine-Containing Peptide Catalysts Developed by a Facile Library Screening Method. Angew. Chem., Int. Ed. 2015, 54, 1822−1826. (8) Misawa, T.; Imamura, M.; Ozawa, Y.; Haishima, K.; Kurihara, M.; Kikuchi, Y.; Demizu, Y. Development of helix-stabilized antimicrobial peptides composed of lysine and hydrophobic α,α-disubstituted αamino acid residues. Bioorg. Med. Chem. Lett. 2017, 27, 3950−3953. (9) Yamashita, H.; Demizu, Y.; Shoda, T.; Sato, Y.; Oba, M.; Tanaka, M.; Kurihara, M. Amphipathic short helix-stabilized peptides with cellmembrane penetrating ability. Bioorg. Med. Chem. 2014, 22, 2403− 2408. (10) Misawa, T.; Kanda, Y.; Demizu, Y. Rational Design and Synthesis of Post-Functionalizable Peptide Foldamers as Helical Templates. Bioconjugate Chem. 2017, 28, 3029−3035. (11) (a) Balcerski, J. S.; Pysh, E. S.; Bonora, G. M.; Toniolo, C. Vacuum ultraviolet circular dichroism of β-forming alkyl oligopeptides. J. Am. Chem. Soc. 1976, 98, 3470−3473. (b) Baron, M. H.; De Loze, C.; Toniolo, C.; Fasman, G. D. Infrared and Raman study in the solid state of fully protected, monodispersed homooligopeptides of L-valine, L-isoleucine, and L-phenylalanine. Biopolymers 1979, 18, 411−424. (c) Toniolo, C. Structural Role of Valine and Isoleucine Residues in Proteins. A Proposal. Macromolecules 1978, 11, 437−438. (d) Toniolo, C.; Bonora, G. M.; Mutter, M. Conformations of poly(ethylene glycol) bound homooligo-L-alanines and -L-valines in aqueous solution. J. Am. Chem. Soc. 1979, 101, 450−454. (e) Toniolo, C.; Bonora, G. M.; Salardi, S. Study of the relationship between conformation and nature of side chains in linear oligopeptides: homologous series derived from β-branched amino acid residues. Int. J. Biol. Macromol. 1981, 3, 377− 383. (f) Narayanan, C.; Dias, C. L. Hydrophobic interactions and

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01030. Crystallographic data and copies of the 1H NMR and 13C NMR spectra of the peptides (PDF) Crystallographic data of peptide 3 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone & Fax: +81-44-270-6578. ORCID

Takashi Misawa: 0000-0002-0339-8750 Yosuke Demizu: 0000-0001-7521-4861 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported, in part, by JSPS KAKENHI grant number 17k08385 (Y.D.), by a grant from the Takeda Science Foundation (Y.D.), a grant from the Terumo Life Science Foundation (Y.D.), a grant from the Suzuken Memorial Foundation (Y.D.), and a grant from the Naito Foundation (Y.D.).

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REFERENCES

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DOI: 10.1021/acsomega.8b01030 ACS Omega 2018, 3, 6395−6399

Article

ACS Omega hydrogen bonds in β-sheet formation. J. Chem. Phys. 2013, 139, 115103. (12) (a) Crisma, M.; Bonora, G. M.; Toniolo, C.; Benedetti, E.; Bavoso, A.; Di Blasio, B.; Pavone, V.; Pedone, C. Structural versatility of peptides from Cα,α-dialkylated glycines: an infrared absorption and 1H n.m.r. study of homopeptides from 1-aminocyclopentane-1carboxylic acid. Int. J. Biol. Macromol. 1988, 10, 300−304. (b) Benedetti, E.; Barone, V.; Bavoso, A.; Di Blasio, B.; Lelj, F.; Pavone, V.; Pedone, C.; Bonora, G. M.; Toniolo, C.; Leplawy, M. T.; Kaczmarek, K.; Redlinski, A. Structural versatility of peptides from Cαα-dialkylated glycines. I. A conformational energy computation and x-ray diffraction study of homo-peptides from Cα,α-diethylglycine. Biopolymers 1988, 27, 357−371. (c) Toniolo, C.; Bonora, G. M.; Bavoso, A.; Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Barone, V.; Lelj, F.; Leplawy, M. T.; Kaczmarek, K.; Redlinski, A. Structural versatility of peptides from C?,?-dialkylated glycines. II. An IR absorption and1H-nmr study of homo-oligopeptides from Cα,αdiethylglycine. Biopolymers 1988, 27, 373−379. (13) (a) Bonora, G. M.; Toniolo, C.; Di Blasio, B.; Pavone, V.; Pedone, C.; Benedetti, E.; Lingham, I.; Hardy, P. Folded and extended structures of homooligopeptides from α,α-dialkylated α-amino acids. An infrared absorption and proton nuclear magnetic resonance study. J. Am. Chem. Soc. 1984, 106, 8152−8156. (b) Toniolo, C.; Bonora, G. M.; Barone, V.; Bavoso, A.; Benedetti, E.; Di Blasio, B.; Grimaldi, P.; Lelj, F.; Pavone, V.; Pedone, C. Conformation of pleionomers of αaminoisobutyric acid. Macromolecules 1985, 18, 895−902. (c) Demizu, Y.; Doi, M.; Kurihara, M.; Maruyama, T.; Suemune, H.; Tanaka, M. One-Handed Helical Screw Direction of Homopeptide Foldamer Exclusively Induced by Cyclic α-Amino Acid Side-Chain Chiral Centers. Chem.Eur. J. 2012, 18, 2430−2439. (14) (a) Toniolo, C.; Polese, A.; Formaggio, F.; Crisma, M.; Kamphuis, J. Circular Dichroism Spectrum of a Peptide 310-Helix. J. Am. Chem. Soc. 1996, 118, 2744−2745. (b) Yoder, G.; Polese, A.; Silva, R. A. G. D.; Formaggio, F.; Crisma, M.; Broxterman, Q. B.; Kamphuis, J.; Toniolo, C.; Keiderling, T. A. Conformational Characterization of Terminally Blockedl-(αMe)Val Homopeptides Using Vibrational and Electronic Circular Dichroism. 310-Helical Stabilization by Peptide− Peptide Interaction. J. Am. Chem. Soc. 1997, 119, 10278−10285. (c) Mammi, S.; Rainaldi, M.; Bellanda, M.; Schievano, E.; Peggion, E.; Broxterman, Q. B.; Formaggio, F.; Crisma, M.; Toniolo, C. Concomitant Occurrence of Peptide 310- and α-Helices Probed by NMR. J. Am. Chem. Soc. 2000, 122, 11735−11736. (15) Demizu, Y.; Okitsu, K.; Yamashita, H.; Doi, M.; Misawa, T.; Oba, M.; Tanaka, M.; Kurihara, M. α-Helical Structures of Oligopeptides with an Alternating l-Leu-Aib Segment. Eur. J. Org. Chem. 2016, 2815−2820. (16) See Supporting Information. (17) Sheldrick, G. M. Program for Crystal Structure Refinement (SHELXL 97); University of Göttingen: Germany, 1997. (18) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; Gelder, R. D.; Israel, R.; Smits, J. M. M. The DIRDIF-99 Program System, Technical Report of the Crystallography Laboratory; University of Nijmegen: The Netherlands, 1994. (19) CCDC-1837130 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www. ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax: (+44) 1223-336-033; or [email protected]). (20) (a) Demizu, Y.; Nagoya, S.; Doi, M.; Sato, Y.; Tanaka, M.; Kurihara, M. Twisted Structure of a Cyclic Hexapeptide Containing a Combination of Alternating l-Leu-d-Leu-Aib Segments. J. Org. Chem. 2012, 77, 9361−9365. (b) Demizu, Y.; Yamashita, H.; Yamazaki, N.; Sato, Y.; Doi, M.; Tanaka, M.; Kurihara, M. Oligopeptides with Equal Amounts of l- and d-Amino Acids May Prefer a Helix Screw Sense. J. Org. Chem. 2013, 78, 12106−12113. (c) Demizu, Y.; Yamashita, H.; Doi, M.; Misawa, T.; Oba, M.; Tanaka, M.; Kurihara, M. Topological Study of the Structures of Heterochiral Peptides Containing Equal Amounts of l-Leu and d-Leu. J. Org. Chem. 2015, 80, 8597−8603.

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DOI: 10.1021/acsomega.8b01030 ACS Omega 2018, 3, 6395−6399